Project Summary The current standard of care for peanut allergy is strict avoidance of peanuts. Due to the contamination of various food items with peanut protein allergens, complete avoidance is difficult to achieve and reduces the quality of life in allergic individuals for fear of accidental ingestion. Upon accidental exposure, allergic individuals must quickly self-administer or receive epinephrine injections and antihistamines to prevent the symptoms associated with the onset of an allergic reaction. To treat peanut allergies, a more recent strategy being tested is allergen-specific immunotherapy which focuses on preventing the development of allergic symptoms by altering the pathologic immune response to non-pathogenic antigens and inducing clinical desensitization which is defined as an increase in the threshold of ingested allergen needed to cause allergic symptoms. Clinical trials investigating long-term oral and sublingual delivery of escalating low doses of peanut proteins as a form of allergen-specific immunotherapy have been conducted and achieved some success at inducing clinical peanut desensitization in peanut-allergic individuals. The effectiveness of oral immunotherapy has been demonstrated by the ability of peanut-allergic patients treated with active oral immunotherapy to tolerate 5,000 mg of peanuts whereas placebo treated patients were only able to tolerate 280 mg of peanuts. However, the daily administration schedule and duration of treatment (>1 year) as well as the occurrence of mild adverse effects such as itching and sneezing and, on rare occasions, severe respiratory reactions, are some of the shortcomings of current peanut-specific mucosal immunotherapy. In addition, although desensitization can be achieved by mucosal immunotherapy, long-term tolerance has yet to be demonstrated as half of the patients who are successfully desensitized regain sensitization after 4 weeks of allergen withdrawal. In summary, the length of time required to achieve clinical desensitization, the potential of experiencing adverse effects associated with peanut-specific mucosal immunotherapy and the short duration of the desensitization of the immune response profile, while providing evidence that allergen-specific immunotherapy can work, suggests that there is still room for improvement by the implementation of novel therapies that reduce the time to desensitization and the possibility of adverse reactions. One strategy for improving current peanut immunotherapy protocols would be to design an immunotherapy formulation that rapidly induces long-lasting peanut-specific Th1 and T regulatory responses while minimizing adverse effects in a hypersensitive host. Sensitization to peanut allergens occurs by the induction of peanut-specific T helper (Th) type 2 cells that secrete Interleukin (IL) -4, -5 and -13 to support B cell production of peanut-specific IgE that binds mast cells (MC) and basophils. The major peanut allergen proteins are Ara h 1, 2, 3 and 6. It is estimated that 95% of peanut allergic individuals have IgE specific for Ara h 1, 2 and 6 and 45% of peanut hypersensitive people have Ara h 3-specific IgE. Exposure to peanut in allergic hosts crosslinks surface IgE on mast cells and basophils inducing their degranulation and secretion of inflammatory mediators that produce allergy symptoms. A recent publication described the ability of injection immunotherapy with peanut extract (PN) adjuvanted with the Toll-like Receptor (TLR)-9 agonist, CpG, to reduce allergic disease severity in mice. Since injection therapy is impractical due to the incidence of severe adverse reactions, mucosal delivery of immunotherapy formulations would be much more acceptable for clinical development. The Staats laboratory at Duke University has recently developed a mouse model of nasal immunotherapy against peanut allergies and shown that a combination of PN adjuvanted with CpG in this mucosal immunization model facilitated a reduction in the severity of peanut-induced anaphylaxis in hypersensitive mice in a manner that is superior to therapy with PN alone. In this SBIR Phase I application, we propose to demonstrate that VesiVax liposome formulations containing immunostimulatory adjuvant molecules that have been shown to stimulate cellular immune responses can be used to re-direct the response of the immune system to an allergen into a non-allergic response profile. We will focus on peanut allergens to demonstrate the proof of concept that VesiVax liposomes can facilitate the switching of the immune response to a non-allergenic response pattern. We will collaborate with Professor Staats? laboratory to conduct these studies.